The heart is composed of diverse muscle and non-muscle cell lineages: atrial/ventricular cardiac myocytes, conduction system cells of the working myocardium, smooth muscle/endothelial cells of the coronary arteries and veins, endocardial cells, valvular components and connective tissue. Congenital heart diseases can arise from defects in the pathways for heart lineage specification, and human degenerative diseases can arise in a subset of ventricular and pacemaker cell lineages. The pathways that guide heart cell lineage diversification are relatively obscure, as the primordial heart precursor cells have not been clearly identified.
Recent work has defined two fields of cardiac progenitors, dubbed the primary and secondary, or anterior heart fields. The primary heart field is believed to give rise to the atria and ventricles of the heart, while the secondary or anterior field is believed to give rise to the outflow tract. The secondary field is believed to reside anterior and dorsal to the heart at the early linear heart tube stage. Initial evidence that the outflow tract of the heart was not present in the linear heart tube came from a series of in vivo lineage studies performed in chick embryos. These studies demonstrated that the outflow tract was not present at the linear heart tube stage, but did not indicate where the outflow tract came from at a later stage.
Recently, the source of the outflow tract has been addressed by studies in chick and mouse embryos. Results of these studies demonstrated that some cells in the outflow tract originate from splanchnic mesoderm adjacent to the pharyngeal endoderm. The extent of the contribution, and the boundaries of the “secondary” or “anterior” heart field could not be definitively assessed from results of these experiments.
Several studies have demonstrated induction of cardiogenic mesoderm in response to inhibition of Wnt signaling in chick, Xenopus and mouse embryos. Wnt antagonists Dickkopf1 and Crescent produced by anterior endoderm in chick embryos stimulate differentiation of cardiogenic mesoderm. In frog embryos, Dkk1 and Crescent secreted by Spemann's organizer are also initiators of cardiac differentiation, acting indirectly on anterior mesendoderm to provoke secretion of an as yet unidentified cardiogenic induction factor. In mouse embryos, ablation of β-catenin utilizing a Cytokeratin19 promoter-driven Cre (K19-Cre) recombinase resulted in ectopic heart formation, which was attributed to ablation of β-catenin in endodermal tissues.
In contrast to the foregoing, activation of Wnt signaling is required for cardiogenesis in Drosophila, and in cell culture systems, including embryonic stem cells, and embryonal carcinoma P19 cells. In these cell culture systems, however, the spatial requirement for Wnt signaling has not been addressed.